Ulcerative colitis (UC) is a chronic inflammatory condition that is immunologically mediated. Approximately 4 million people world-wide have the disease and are at increased colon cancer risk. Conventional treatment of colitis can reduce periods of active disease and help to maintain remission, but these treatments are often associated with side effects and have marginal results. For this reason, many colitis sufferers turn to complementary and alternative treatments in hopes of abating symptoms of active disease. It is estimated that about 50% of UC patients use some form of megavitamin therapy or herbal/dietary supplement. There is, however, no documentation on UC patients taking American ginseng to temper the signs and symptoms of colitis. In the current study, we present exciting data that ginseng inhibits the onset of colitis in two mouse models of colitis as well as preventing colitis-driven colon cancer. This grant aims to understand the mechanisms of this inhibition as a necessary pre-requisite to future human clinical trials. We will test the hypothesis that dietary supplementation with American ginseng inhibits UC-associated inflammation in the colon through mechanisms involving induction of apoptosis in immune cells, altered Th1/Th2 cytokine profiles, and/or changes in immune cell migration and trafficking. Because ginseng also inhibits the colitisto- cancer sequence in our model, we will examine whether it suppresses inflammation-driven DMA damage and protein nitration in colon cells. Because pRb is hyperphosphorylated and inactivated in colitis, we will further examine whether ginseng suppresses pRb hyperphosphorylation through mechanisms involving a decrease in the activation of specific kinase pathways. We will investigate whether ginseng mediates these effects through direct action on the colon cells and/or on immune cells. Finally, we propose to delineate the active ingredients of American ginseng responsible for the inhibition of colitis. Together, this study will increase our understanding of how American ginseng protects from colitis, and possibly other autoimmune conditions and will provide the rationale for expanding into clinical trials.